(1) Field of the Invention
The present invention relates to a process for the preparation of o-(2,6-dichloroanilino)phenylacetic acid represented by the following formula (III): ##STR1## which is broadly used under the general name of "Diclofenac" as a non-steroidal analgesic anti-inflammatory agent, and its pharmacologically acceptable acid addition salt, and also to a novel intermediate for use in the preparation of Diclofenac, which is represented by the following general formula (I): ##STR2## where R.sub.1 and R.sub.2, which may be the same or different, stand for a lower alkyl group, or one of R.sub.1 and R.sub.2 stands for a lower alkyl group and the other of R.sub.1 and R.sub.2 stands for a phenyl or benzyl group, or R.sub.1 and R.sub.2 are bonded together to form a heterocyclic ring together with a nitrogen atom and/or and oxygen atom; and X stands for an iodine or bromine atom.
(2) Description of the Prior Art
Various processes for the preparation of o-(2,6-dichloroanilino)phenylacetic acid have been proposed. Some of them are described below.
(a) Japanese Patent Publication No. 27374/59 (British Pat. No. 1,139,332, Ciba-Geigy) discloses a process comprising hydrolyzing a nitrile represented by the following formula: ##STR3## with an alkali metal hydroxide in an aqueous medium at the boiling point thereof form a compound represented by the following formula: ##STR4##
In the foregoing formulae, R.sup.1 stands for a hydrogen or halogen atom or an alkyl group, R.sup.2 stands for a hydrogen or halogen atom or an alkyl or trifluoromethyl group, R.sup.3 stands for a hydrogen or halogen atom or an alkyl group, with the proviso that the case where all of R.sup.1, R.sup.2 and R.sup.3 stand for a hydrogen atom is excluded, R.sup.4 stands for a hydrogen or halogen atom or an alkyl group, R.sup.5 stands for a hydrogen atom or an alkyl group, R.sup.6 stands for a hydrogen atom and A stands for a hydrogen atom or an acyl group, particularly an alkanoyl group.
(b) Japanese Patent Publication No. 11295/70 (Ciba-Geigy) discloses a process comprising hydrolyzing an ester represented by the following formula: ##STR5## with an alkali metal hydroxide, an alkali metal carbonate or an alkali metal bicarbonate in the presence of a basic ion exchanger to form a compound represented by the following formula: ##STR6##
In the foregoing formulae, R.sup.1 stands for a hydrogen or halogen atom or an alkyl group, R.sup.2 stands for a hydrogen or halogen atom or a alkyl or trifluoromethyl group, R.sup.3 stands for a hydrogen or halogen atom or an alkyl or alkoxy group, with the proviso that the case where all of R.sup.1, R.sup.2 and R.sup.3 stand for a hydrogen atom is excluded, R.sup.4 stands for a hydrogen or halogen atom, R.sup.5 stands for a hydrogen atom or an alkyl group, R.sup.6 stands for an alkyl or aralkyl group, particularly a benzyl group, and A stands for an acyl group, particularly an alkanoyl group.
(c) Japanese Patent Application Laid-Open Specification No. 71439/77 (Nippon Chemiphar Co., Ltd.) discloses a process comprising reacting a compound represented by the following formula: ##STR7## with a compound represented by the following formula: ##STR8## in the presence of a copper catalyst in a solvent to obtain a compound of the following formula: ##STR9## in a yield of 13 to 18%.
In the foregoing formulae, Y stands for a halogen atom or an amino group and X stands for an amino group or a halogen atom.
(d) Japanese Patent Application Laid-Open Specification No. 7640/78 (Teikoku Hormone Mfg. Co., Ltd.) discloses a process comprising reacting a compound of the following formula: ##STR10## with a compound of the following formula: ##STR11## in the presence of a copper catalyst in a solvent to form a compound of the following formula: ##STR12## in a yield of 40 to 83%, and if necessary, saponifying the so obtained compound under alkaline conditions to obtain a compound represented by the following formula: ##STR13## In the foregoing formulae, R.sub.1 stands for a hydrogen atom or a methyl group, and R.sub.2 stands for a methyl, propyl or a t-butyl group.
All of these known processes, however, are industrially insufficient and defective because the number of steps to Diclofenac is very large and the yield is extremely low at one or more of these many steps.